GB632395A - Improvements in or relating to 6-substituted thiouracil compounds and process of preparing the same - Google Patents

Abstract

6-Cycloalkyl- or 6-alkylcycloalkyl-2-thiouracils are prepared by condensing thiourea with a b -cycloalkyl- or b -alkylcycloalkyl-b -oxopropionic acid ester, wherein the cycloalkyl- or alkylcycloalkylradical has 3-5 carbon atoms, in the presence of a strong base as a condensing agent, such as an alkali metal alkoxide. The cycloalkyl radical may suitably be a cyclopropyl or alkyl cyclopropyl radical, a cyclobutyl or methylcyclobutyl radical or a cyclopentyl radical. The compounds of the invention may be converted into salts by treatment with bases, e.g. alkali metal hydroxides, ammonia or alkaline earth hydroxides. In examples: (1) ethyl b -cyclopropyl-b -oxopropionate is added to thiourea in alcohol in the presence of sodium ethoxide to give 6-cyclopropyl-2-thiouracil; (2) ethyl b -cyclobutyl-b -oxopropionate is reacted with thiourea as in (1) to give 6-cyclobutyl-2-thiouracil; and (3) ethyl b -cyclopentyl-b -oxopropionate is reacted with thiourea as in (1) to give 6-cyclopentyl-2-thiouracil. Cycloalkyl-oxopropionic esters may be prepared by the condensation of a cycloalkyl methyl ketone with diethyl carbonate in the presence of a metallating agent such as sodamide or in the presence of sodium ethoxide; by the reaction of diethyl oxalate with a cycloalkyl methyl ketone to give a substituted glyoxylic acid ester which is then heated to lose carbon monoxide; by the condensation of a cycloalkyl carbonyl halide with ethyl acetoacetate, followed by removal of the acetyl group; or by reaction of a cycloalkyl carbonyl halide with malonic ester in the presence of a basic catalyst followed by removal of one carbethoxy group; e.g. ethyl b -cyclopropyl-b -oxopropionate is prepared by reacting cyclopropylmethyl ketone with diethyl carbonate in the presence of sodamide or by condensing cyclopropane carbonyl p chloride with ethyl acetoacetate followed by treatment with gaseous ammonia; ethyl b -cyclobutyl-b -oxopropionate is prepared by reacting cyclobutane carbonyl chloride with ethyl acetoacetate followed by ammonia treatment and ethyl b -cyclopentyl-b -oxopropionate is similarly prepared from cyclopentane carbonyl chloride and ethyl acetoacetate. Cyclopropane carbonyl chloride is prepared by treating g -chlorobutyronitrle with potassium hydroxide to give cyanocyclopropane which is hydrolysed to the carboxylic acid and treated with thionyl chloride to give the acid chloride. Cyclobutane carbonyl chloride is prepared by reacting cyclobutane carboxylic acid with thionyl chloride. Cyclopentane carbonyl chloride is prepared by adding sodium in alcohol to a -chlorocyclohexanone to give cyclopentane carboxylic acid which reacts with thionyl chloride to give the acid halide. Specification 452,043, [Group XX], is referred to.